NCI 6896: A phase I trial of suberoylanilide hydroxamic acid (SAHA) and 13-cis retinoic acid in the treatment of patients with advanced renal cell carcinoma (RCC).

Abstract

349 Background: Retinoid resistance in RCC inversely correlates with levels of intracellular retinol and retinyl esters suggesting that increasing intracellular levels of all-trans retinoic acid (RA) or enabling RA to become a more potent initiator of transcription will improve RA mediated anti-tumor effects. The combination of all-trans RA and a histone deacetylase (HDAC) inhibitor inhibited renal cancer cell proliferation and tumor growth in a xenograft model more than either drug alone. We performed a phase I clinical trial to evaluate the safety and preliminary efficacy of combining the oral HDAC inhibitor SAHA (vorinostat) plus oral 13-cis RA (isotretinoin) in patients with advanced RCC. Secondary endpoints include analysis of peripheral blood samples to study the effects on retinoid metabolites and retinoid related genes. Methods: Patients (pts) with metastatic RCC (any histology) who have failed at least two lines of prior therapy were eligible. Vorinostat (300 mg bid x 3 consecutive days per week + isotretinoin co-administered at 0.25 mg/kg, 0.375 mg/kg, or 0.5 mg/kg PO bid x 3 days per week in cohorts using standard 3+3 dose escalation. Dose limiting toxicity (DLT) was defined as any grade > 3 toxicity during the first cycle. Results: 14 pts have enrolled on the trial of which 12 are evaluable for toxicity (6 cohort 1; 3 cohort 2; 3 cohort 3) and 11 for tumor response. Common grade 1-2 toxicities included fatigue and GI effects (nausea, diarrhea, anorexia). One pt on dose-level 1 experienced a DLT (grade 3 depression). One patient experienced a partial response and 10 patients had stable disease lasting a median of 4 months (range 2–10 mos). Three patients progressed with brain metastases in the setting of stable systemic disease for at least 6 months. Pharmacokinetic and correlative studies examining expression of retinoid related genes are ongoing. Conclusions: The recommended phase II dose is vorinostat (300 mg bid) + isoretinoin (0.5 mg/kg PO bid) 3 days per week. The combination of vorinostat and isotretinoin was well tolerated, and there was evidence of antitumor activity in this heavily pretreated population of patients with refractory metastatic RCC. [Table: see text]